Epithelial stem and progenitor cells in the postnatal mouse lung
Lead Research Organisation:
University of Cambridge
Department Name: Gurdon Institute
Abstract
Our bodies are constantly undergoing maintenance work in order to sustain normal organ function. In the lung this maintenance is carried out by progenitor cells which are able to divide to replace old or damaged cells. The behaviour of these progenitor cells must be tightly controlled so that our lungs always have the correct numbers and types of different cells. The structure of the lung is altered in many human lung conditions and this is likely to be a contributing factor to various lung diseases. It is therefore important to understand the progenitor cell system both in normal adult lungs and models of human lung conditions. I have developed a panel of genetically modified mice which allow me to manipulate gene expression in lung epithelial progenitors. I propose to use these mice to:
1. Distinguish between sub-sets of progenitor cells which are thought to have different roles in normal lung maintenance.
2. Identify the genetic mechanisms which regulate the behaviour of progenitor cells in the normal adult lung.
This knowledge will greatly enhance our understanding of normal lung function, and changes associated with various diseases. Ultimately it could lead to the development of methods to prevent or cure these diseases.
1. Distinguish between sub-sets of progenitor cells which are thought to have different roles in normal lung maintenance.
2. Identify the genetic mechanisms which regulate the behaviour of progenitor cells in the normal adult lung.
This knowledge will greatly enhance our understanding of normal lung function, and changes associated with various diseases. Ultimately it could lead to the development of methods to prevent or cure these diseases.
Technical Summary
Adult organs are maintained for the lifespan of an individual. There are two main models for how this is achieved. One, through the function of stem cells which both self-renew and produce differentiated daughters throughout the lifetime of the organ, such as in the intestine. Two, through the self-renewal of differentiated cells, such as in the liver. How is the long-term maintenance of the lung epithelium achieved? My hypothesis is that the lung uses a region-specific combination of both mechanisms. Moreover, that the behaviour of the adult progenitor cells is controlled by similar mechanisms to lung embryonic progenitors. To address these questions, I have developed a panel of genetic tools that can be used either for lineage-labelling or manipulation of gene expression in different mouse lung epithelial cell types, including progenitor cells. These genetic tools will be used in combination with mouse models of lung injury to better characterize lung epithelial stem and progenitor cells and to define their contribution to lung disease. Specifically, I have two independent, but inter-related goals:
1. To employ single-cell lineage-analysis of known progenitor cell types in the lung epithelium to test the hypothesis that particular sub-sets of these cells are niche-localized stem cells. An analysis of patterns of progenitor cell division will also be performed.
2. To test the hypothesis that the same pathways which control the behaviour of mouse embryonic lung epithelial progenitors are re-used in the adult. The effects of manipulating Notch and FGF Receptor signalling in single stem or progenitor cells will be investigated.
One in seven people in the UK live with some form of lung disease (British Lung Foundation). Many of these human conditions can be neither controlled nor cured, and their aetiology remains a mystery. The cellular composition of the human lung epithelium has been observed to change during the development of many conditions, including asthma, emphysema and pulmonary fibrosis. For example, there is evidence for changes in the epithelial repair process in both children and adults with asthma. It has been hypothesized that these changes contribute to the development or the severity of the disease. A greater understanding of the mechanisms that regulate how new cells are formed from progenitor or stem cells in the lung will help us to understand exactly how these, and other, lung conditions develop and will contribute significantly to the search for improved treatments.
1. To employ single-cell lineage-analysis of known progenitor cell types in the lung epithelium to test the hypothesis that particular sub-sets of these cells are niche-localized stem cells. An analysis of patterns of progenitor cell division will also be performed.
2. To test the hypothesis that the same pathways which control the behaviour of mouse embryonic lung epithelial progenitors are re-used in the adult. The effects of manipulating Notch and FGF Receptor signalling in single stem or progenitor cells will be investigated.
One in seven people in the UK live with some form of lung disease (British Lung Foundation). Many of these human conditions can be neither controlled nor cured, and their aetiology remains a mystery. The cellular composition of the human lung epithelium has been observed to change during the development of many conditions, including asthma, emphysema and pulmonary fibrosis. For example, there is evidence for changes in the epithelial repair process in both children and adults with asthma. It has been hypothesized that these changes contribute to the development or the severity of the disease. A greater understanding of the mechanisms that regulate how new cells are formed from progenitor or stem cells in the lung will help us to understand exactly how these, and other, lung conditions develop and will contribute significantly to the search for improved treatments.